Selective inhibition of interleukin 6 receptor decreased inflammatory cytokines and increased proteases in an experimental model of critical calvarial defect.

Considering the lack of consensus related to the impact of selective IL-6 receptor inhibition on bone remodeling and the scarcity of reports, especially on large bone defects, this study proposed to evaluate the biological impact of the selective inhibitor of interleukin-6 receptor (tocilizumab) in an experimental model of critical calvarial defect in rats. In this preclinical and in vivo study, 24 male Wistar rats were randomly divided into two groups (n=12/group): defect treated with collagen sponge (CG) and defect treated with collagen sponge associated with 2 mg/kg tocilizumab (TCZ). The defect in the parietal bone was created using an 8-mm diameter trephine drill. After 90 days, the animals were euthanized, and tissue samples (skull caps) were evaluated through micro-CT, histological, immunohistochemistry, cytokines, and RT-qPCR analyses. Tocilizumab reduced mononuclear inflammatory infiltration (P<0.05) and tumor necrosis factor (TNF)-α levels (P<0.01) and down-regulated tissue gene expression of BMP-2 (P<0.001), RUNX-2 (P<0.05), and interleukin (IL)-6 (P<0.05). Moreover, it promoted a stronger immunostaining of cathepsin and RANKL (P<0.05). Micro-CT and histological analyses revealed no impact on general bone formation (P>0.05). The bone cells (osteoblasts, osteoclasts, and osteocytes) in the defect area were similar in both groups (P>0.05). Tocilizumab reduced inflammatory cytokines, decreased osteogenic protein, and increased proteases in a critical bone defect in rats. Ninety days after the local application of tocilizumab in the cranial defect, we did not find a significant formation of bone tissue compared with a collagen sponge.

Grb2 Y160F mutant mimics the wild-type monomeric state dynamics and the monomer-dimer equilibrium.

The Growth factor receptor-bound protein 2 (Grb2) participates in early signaling complexes and regulates tyrosine kinase-mediated signal transduction through a monomer-dimer equilibrium. Grb2 dimeric state inhibits signal transduction whereas the monomer promotes signaling downstream. Since Grb2 dimer KD is ∼0.8 µM, studies focused on the monomer are still challenging and require mutations or interaction with phosphotyrosine peptides. However, these mutants were never characterized considering their effects on protein structure and dynamics in solution. Here, we present the biophysical characterization of Grb2Y160F, the first Grb2 mutant to induce protein monomerization without disrupting its native behavior in solution due to net charge modifications or interaction with peptides. We also identified that Grb2Y160F exists in a monomer-dimer equilibrium. Grb2Y160F ability to dimerize implies that different dimerization interfaces might regulate signaling pathways in distinct ways and raises an important question about the role of the Y160 residue in other dimerization interfaces.

Cisplatin and ototoxicity in childhood: the perspective of supporting otoprotective agentes.

Cisplatin is an antineoplastic medicine used in the treatment for various types of cancer. Among its side effects is ototoxicity, which may result in a bilateral and irreversible hearing loss. The ototoxic effect in the pediatric population has a bigger impact as it compromises language acquisition. The discovery of drugs with otoprotective effects and the optimal way to administer them have become significant challenges in minimizing the impact of cisplatin regarding auditory function. The objective was to understand otoprotective drugs and their relevance in the preventive treatment to cisplatin-induced ototoxicity in childhood. An integrative review was conducted by consulting databases including PubMed, Bireme, MedLine, LILACS, SciELO, and ClinicalTrials.gov. The search strategy was performed by crossing descriptors (DeCS and MeSH) and free terms. Studies published in English, Spanish, and Portuguese were selected, with no publication year restrictions. Subsequently, articles were selected according to inclusion and exclusion criteria. A total of 736 articles were found in PubMed, 431 in Bireme, 425 in MedLine, 6 in LILACS, 0 in SciELO, and 4 in ClinicalTrials.gov. After document analysis, 12 articles were selected for full analysis. Evidence was found for 8 substances with potential otoprotective effects when used with cisplatin, which tend to minimize the impact of cisplatin regarding auditory function. The substances found were: Amifostine, Dexamethasone, Genistein, Ginkgo Biloba, Lycopene, N-acetylcysteine, Polydatin also Sodium Thiosulfate. In general, these drugs are applied before, during, or after cisplatin infusion, depending on the chosen drug, via intravenous, oral, or transtympanic injections, acting as antioxidant therapy. The biochemical effects of these substances are relevant to their potential otoprotective properties, including the inactivation of oxygen free radicals and electrophilic platinum species. The use of these substances can reduce ototoxicity, decreasing cisplatin-induced hearing loss and improving the confort of life, especially for children.

Guarana (Paullinia cupana) as a potential tool for mesenchymal stromal cells priming in regenerative medicine.

Mesenchymal stromal cells (MSCs) have therapeutic potential due to their abilities of differentiation, immunomodulation, and migration to injured tissues, potentiating such effects when cells are activated. Guarana (Paullinia cupana) is a tropical plant species found in South America that is known for its antioxidant, stimulant, and cicatricial effects. The guarana extract is composed of many substances and caffeine is the main component. The objective was to evaluate the effects of guarana and caffeine on MSCs. After the initial characterization, MSCs were treated with Paullinia cupana (10, 100, and 1000 µg/mL) or caffeine (0.4, 4, and 40 µg/mL) for 24 h. MSCs treatment with 1000 µg/mL guarana increased cell polarity, viability, cell migration to chemoattractant, antioxidant potential, and liberation of extracellular vesicles (EVs), while it reduced the levels of autophagy. MSCs treated with 100 and 1000 µg/mL guarana or 40 µg/mL caffeine showed a decrease of cell proliferation. No treatment affected the cellular area and cell cycle of MSCs. The study shows in vitro evidence that guarana could be a promising alternative for activating MSCs to promote better cellular products for future clinical therapies.

Tobacco smoking and tooth loss in adults and elderly in Brazil: a populational-based cross-sectional study.

OBJECTIVES: To determine the association between smoking and tooth loss in individuals aged 18 years or more living in Brazil. METHODS: Secondary analysis of the 2019 Brazilian National Health Survey data. The outcome was self-reported tooth loss, and the main independent variable was tobacco smoking. Family income, schooling, sex and age were covariates. Multiple linear regression analysis determined the association between tobacco smoking and the number of missing teeth and then the average number of missing teeth was predicted according to smoking status. RESULTS: The mean number of missing teeth in 88,531 individuals aged 18 or more was 7.7 (95%CI: 7.6-7.8). At least one missing tooth was identified in 72.0% (95%CI: 71.4-72.6) of the population, 21.3% (95%CI: 20.9-21.7) had a non-functional dentition, 14.2% (95%CI: 13.9-14.6) had severe tooth loss and 10.3% (95%CI: 10.0-10.6) were edentulous. The adjusted regression coefficients for number of missing teeth showed that current or former smokers, individuals with low family income and schooling, older age and females exhibited higher tooth loss. Current and former smokers had 1.40 (95%CI: 1.35-1.46) and 1.13 (95%CI: 0.54-0.98) times more lost teeth than never smokers, respectively. CONCLUSIONS: Both tooth loss and smoking are common in Brazilians and are associated. Unfavorable socioeconomic status and demographic factors also predict tooth loss.

Insights into incipient oral squamous cell carcinoma: a comprehensive south-american study.

BACKGROUND: To describe demographic and clinicopathological aspects of a South-American cohort of incipient oral squamous cell carcinoma patients. MATERIAL AND METHODS: A cross-sectional, observational study was performed to assess demographic and clinicopathological characteristics of incipient oral squamous cell carcinoma patients from 6 South-American institutions. RESULTS: One hundred and seven patients within the histopathological spectrum of incipient oral squamous cell carcinoma (in-situ and microinvasive) were included. Fifty-eight (54.2%) patients were men with a mean age of 60.69 years. Forty-nine (45.8%) and thirty-nine (36.5%) patients had history of tobacco and alcohol use, respectively. Clinically, most of the lesions were plaques (82.2%), ≥ 2 cm in extension (72%), affecting the lateral border of the tongue (55.1%), and soft palate (12.1%) with a mixed (white and red) appearance. Eighty-two (76.7%) lesions were predominantly white and 25 (23.3%) predominantly red. CONCLUSIONS: To the best of our knowledge, this is the largest cohort of incipient oral squamous cell carcinoma patients, which raises awareness of clinicians' inspection acuteness by demonstrating the most frequent clinical aspects of this disease, potentially improving oral cancer secondary prevention strategies.

Dental pain in Brazilian preschool children: association with the severity of dental caries and impact on oral health-related quality of life.

PURPOSE: This study aimed to verify the association between dental pain and severity of dental caries (caries morbidity stages) and the impact on oral health-related quality of life (OHRQoL) in preschool children. METHODS: A cross-sectional study with 199 children (2-5 years old) enrolled at preschools in Capão do Leão-RS, Brazil. The self-report of mothers of children with a history of dental pain in the last 6 months and perception of their child's OHRQoL (ECOHIS) were obtained through a structured questionnaire. This questionnaire also collected independent variables. Children's oral examination was performed using the CAST instrument to determine caries morbidity stage. Crude and adjusted Poisson regression analysis was performed. RESULTS: The prevalence of dental pain was 14.57%. The chance of the occurrence of dental pain was higher among children diagnosed in morbidity [Prevalence ratio-PR: 5.29 (95% confidence interval-95% CI 1.91-14.61); p = 0.001] and severe morbidity [RP = 6.12 (95 CI% 2.25-16.64); p < 0.001] stages. Children with dental pain presented higher scores in the total ECOHIS [rate ratio = 7.11 (95% CI 4.55-11.09); p < 0.001] and in all of the domains of this instrument. Furthermore, children with a history of dental trauma [PR = 2.41 (95% CI 1.15-5.04); p < 0.001] and those whose reason for last visit to the dental office was for restorative/endodontic/extraction treatment [PR = 1.29 (95% CI 1.01-6.19); p = 0.049] had a higher prevalence of dental pain. CONCLUSION: A substantial prevalence of dental pain in the last 6 months and negative impact on children's OHRQoL was identified in this sample. Children diagnosed with carious dentin lesions and abscess and fistula were more likely to have dental pain.

Management of infusion-related reactions in cancer therapy: strategies and challenges.

Several anticancer therapies have the potential to cause infusion-related reactions (IRRs) in the form of adverse events that typically occur within minutes to hours after drug infusion. IRRs can range in severity from mild to severe anaphylaxis-like reactions. Careful monitoring at infusion initiation, prompt recognition, and appropriate clinical assessment of the IRR and its severity, followed by immediate management, are required to ensure patient safety and optimal outcomes. Lack of standardization in the prevention, management, and reporting of IRRs across cancer-treating institutions represents not only a quality and safety gap but also a disparity in cancer care. The present article, supported by recently published data, was developed to standardize these procedures across institutions and provide a useful tool for health care providers in clinical practice to recognize early signs and symptoms of an IRR and promptly and appropriately manage the event.

Guarana (Paullinia cupana) as a potential tool for mesenchymal stromal cells priming in regenerative medicine

Mesenchymal stromal cells (MSCs) have therapeutic potential due to their abilities of differentiation, immunomodulation, and migration to injured tissues, potentiating such effects when cells are activated. Guarana (Paullinia cupana) is a tropical plant species found in South America that is known for its antioxidant, stimulant, and cicatricial effects. The guarana extract is composed of many substances and caffeine is the main component. The objective was to evaluate the effects of guarana and caffeine on MSCs. After the initial characterization, MSCs were treated with Paullinia cupana (10, 100, and 1000 μg/mL) or caffeine (0.4, 4, and 40 μg/mL) for 24 h. MSCs treatment with 1000 μg/mL guarana increased cell polarity, viability, cell migration to chemoattractant, antioxidant potential, and liberation of extracellular vesicles (EVs), while it reduced the levels of autophagy. MSCs treated with 100 and 1000 μg/mL guarana or 40 μg/mL caffeine showed a decrease of cell proliferation. No treatment affected the cellular area and cell cycle of MSCs. The study shows in vitro evidence that guarana could be a promising alternative for activating MSCs to promote better cellular products for future clinical therapies.

Selective inhibition of interleukin 6 receptor decreased inflammatory cytokines and increased proteases in an experimental model of critical calvarial defect

Considering the lack of consensus related to the impact of selective IL-6 receptor inhibition on bone remodeling and the scarcity of reports, especially on large bone defects, this study proposed to evaluate the biological impact of the selective inhibitor of interleukin-6 receptor (tocilizumab) in an experimental model of critical calvarial defect in rats. In this preclinical and in vivo study, 24 male Wistar rats were randomly divided into two groups (n=12/group): defect treated with collagen sponge (CG) and defect treated with collagen sponge associated with 2 mg/kg tocilizumab (TCZ). The defect in the parietal bone was created using an 8-mm diameter trephine drill. After 90 days, the animals were euthanized, and tissue samples (skull caps) were evaluated through micro-CT, histological, immunohistochemistry, cytokines, and RT-qPCR analyses. Tocilizumab reduced mononuclear inflammatory infiltration (P<0.05) and tumor necrosis factor (TNF)-α levels (P<0.01) and down-regulated tissue gene expression of BMP-2 (P<0.001), RUNX-2 (P<0.05), and interleukin (IL)-6 (P<0.05). Moreover, it promoted a stronger immunostaining of cathepsin and RANKL (P<0.05). Micro-CT and histological analyses revealed no impact on general bone formation (P>0.05). The bone cells (osteoblasts, osteoclasts, and osteocytes) in the defect area were similar in both groups (P>0.05). Tocilizumab reduced inflammatory cytokines, decreased osteogenic protein, and increased proteases in a critical bone defect in rats. Ninety days after the local application of tocilizumab in the cranial defect, we did not find a significant formation of bone tissue compared with a collagen sponge.

Unresectable stage III non-small cell lung cancer: Insights from a Portuguese expert panel.

INTRODUCTION: The management of unresectable stage III non-small cell lung cancer (NSCLC) is clinically challenging and there is no current consensus on optimal strategies. Herein, a panel of Portuguese experts aims to present practical recommendations for the global management of unresectable stage III NSCLC patients. METHODS: A group of Portuguese lung cancer experts debated aspects related to the diagnosis, staging and treatment of unresectable stage III NSCLC in light of current evidence. Recent breakthroughs in immunotherapy as part of a standard therapeutic approach were also discussed. This review exposes the major conclusions obtained. RESULTS: Practical recommendations for the management of unresectable stage III NSCLC were proposed, aiming to improve the pathways of diagnosis and treatment in the Portuguese healthcare system. Clinical heterogeneity of patients with stage III NSCLC hinders the development of single standardised algorithm where all fit. CONCLUSIONS: A timely diagnosis and a proper staging contribute to the best management of each patient, optimizing treatment tolerance and effectiveness. The expert panel considered chemoradiotherapy as the preferable approach when surgery is not possible. Management of adverse events and immunotherapy as a consolidation therapy are also essential steps for a successful strategy.

Inferring the diurnal variability of OH radical concentrations over the Amazon from BVOC measurements.

The atmospheric oxidation of biogenic volatile organic compounds (BVOC) by OH radicals over tropical rainforests impacts local particle production and the lifetime of globally distributed chemically and radiatively active gases. For the pristine Amazon rainforest during the dry season, we empirically determined the diurnal OH radical variability at the forest-atmosphere interface region between 80 and 325 m from 07:00 to 15:00 LT using BVOC measurements. A dynamic time warping approach was applied showing that median averaged mixing times between 80 to 325 m decrease from 105 to 15 min over this time period. The inferred OH concentrations show evidence for an early morning OH peak (07:00-08:00 LT) and an OH maximum (14:00 LT) reaching 2.2 (0.2, 3.8) × 106 molecules cm-3 controlled by the coupling between BVOC emission fluxes, nocturnal NOx accumulation, convective turbulence, air chemistry and photolysis rates. The results were evaluated with a turbulence resolving transport (DALES), a regional scale (WRF-Chem) and a global (EMAC) atmospheric chemistry model.

Efficacy and safety of fluoroless ureteroscopy and retrograde intrarenal surgery for the treatment of urolithiasis: A comparative study.

INTRODUCTION: Ureteroscopy (URS) and retrograde intrarenal surgery (RIRS) are traditionally guided by fluoroscopy, but the risks of exposure to ionizing radiation may present a matter of concern for patients and urologists. The aim of this study was to evaluate the efficacy and safety of fluoroless URS and RIRS compared with conventional fluoroscopy-guided procedures for the treatment of ureteral and renal stones. MATERIAL AND METHODS: Patients treated with URS or RIRS for urolithiasis between August 2018 and December 2019 were retrospectively evaluated and grouped according to the use of fluoroscopy. Data was collected from individual patient records. The main outcomes were stone-free rate (SFR) and complications, compared between the fluoroscopy and fluoroless groups. A subgroup analysis by type of procedure (URS and RIRS) and a multivariate analysis to identify predictors of residual stones were conducted. RESULTS: A total of 231 patients met the inclusion criteria: 120 (51.9%) in the conventional fluoroscopy group and 111 (48.1%) in the fluoroless group. No significant differences were found between groups regarding SFR (82.5% vs 90.1%, p=.127) or postoperative complication rate (35.0% vs 31.5%, p=.675). In the subgroup analysis these variables did not present significant differences, regardless of the procedure considered. In the multivariate analysis the fluoroless technique was not an independent predictor of residual lithiasis (OR 0.991; 95% IC 0.407-2.411; p=.983), when adjusted for procedure type, stone size and stone number. CONCLUSION: URS and RIRS can be done without fluoroscopic guidance in selected cases, without affecting the efficacy or safety of the procedure.

Splinting in the management of dental trauma in the primary dentition: a systematic review.

PURPOSE: The purpose of this study was to gather existing data on the efficacy of tooth splinting (TS) in patients with traumatized primary teeth, evaluating their overall prognosis and reported complications. METHODS: Electronic searches were performed in seven databases up to Februray/2023. Clinical studies published in the last two decades and presenting the following characteristics were included: (a) reporting on children with traumatized primary teeth; (b) describing the efficacy of splinting those teeth. Studies describing imobilization of dental avulsion were excluded. RESULTS: A total of 163 potentially relevant studies were initially found. After title/abstract screening, and full-text evaluation, three retrospective studies with moderate to high risk of bias were included. The studies described the outcomes of TS in primary teeth with luxation (intrusion, extrusion, lateral displacement), intra-alveolar root fracture, and/or alveolar fracture. High clinical success rate was observed for teeth with root fracture. Benefits of spliting teeth with lateral luxation were not identified, although it may be a reccomended approach. No study was found evaluating TS for alveolar fracture. CONCLUSION: Based on a low level of evidence, the findings highlight a better clinical success rate of the use of TS in the management of deciduous teeth with root fractures.

Rare RNF213 variant in adolescent with moyamoya disease. / Variante rara de RNF213 en adolescente con enfermedad de moyamoya.

INTRODUCTION: Moyamoya disease is a progressive steno-occlusive disease of the major intracranial arteries. Affected individuals are at risk for intracranial hemorrhagic or ischemic stroke, cognitive impairment, and developmental delays. Several susceptibility genes have been identified. The p.R4810K variant in the RNF213 gene has been identified in 95% of patients with familial moyamoya disease. CASE REPORT: We present the case of a 15-year-old adolescent girl who presented with chief complaints of dysgraphia, lack of coordination in the right hand, with two months of evolution. Cerebral magnetic resonance imaging revealed several ischemic lesions with different rates of evolution and magnetic resonance angiography showed multiple subocclusive stenoses. In the study of the sequences of the coding regions and intronic flanking regions (±8 bp) of the RNF213 gene, the variant c.12185G>A, p.(Arg4062Gln) was detected in heterozygosity in the RNF213 gene. This result indicates that the patient is heterozygous for the c.12185G>A, p.(Arg4062Gln) variant in the RNF213 gene. The detected variant has already been reported in the literature as a founder variant in the Asian population, associated with moyamoya syndrome. This variant is described in ClinVar as a variant of unknown clinical significance? Furthermore, it is not described in population databases (dbSNP, ESP, gnomAD). CONCLUSION: To our knowledge, the p.(Arg406262Gln) variant has been reported in three Japanese moyamoya disease patients and one European. Therefore, our patient was the second European moyamoya disease patient with this variant identified.

TITLE: Variante rara de RNF213 en adolescente con enfermedad de moyamoya.Introducción. La enfermedad de moyamoya es una enfermedad estenooclusiva progresiva de las principales arterias intracraneales. Los individuos afectados corren el riesgo de sufrir un accidente cerebrovascular hemorrágico o isquémico intracraneal, deterioro cognitivo y retrasos en el desarrollo. Se han identificado varios genes de susceptibilidad. La variante p.R4810K en el gen RNF213 se ha identificado en el 95% de los pacientes con enfermedad de moyamoya familiar. Caso clínico. Presentamos el caso de una adolescente de 15 años que se presentó con quejas principales de disgrafía y falta de coordinación en la mano derecha con dos meses de evolución. La resonancia magnética cerebral reveló varias lesiones isquémicas con diferentes ritmos de evolución y la angiorresonancia magnética mostró múltiples estenosis suboclusivas. En el estudio de las secuencias de las regiones codificantes y de las regiones intrónicas flanqueantes (±8 pb) del gen RNF213, se detectó la variante c.12185G>A, p.(Arg4062Gln) en heterocigosidad en el gen RNF213. Este resultado indica que la paciente es heterocigota para la variante c.12185G>A, p.(Arg4062Gln) en el gen RNF213. La variante detectada ya ha sido descrita en la bibliografía como una variante fundadora en la población asiática, asociada a síndrome de moyamoya. Esta variante está descrita en ClinVar como una variante de significado clínico desconocido. Además, no está descrita en las bases de datos poblacionales (dbSNP, ESP y gnomAD). Conclusión. Hasta donde sabemos, la variante p.(Arg4062Gln) se ha notificado en tres pacientes japoneses con enfermedad de moyamoya y en uno europeo. Por lo tanto, nuestro paciente fue el segundo europeo con enfermedad de moyamoya con esta variante identificada.

Lung cancer survival and sex-specific patterns in Portugal: A population-based analysis.

INTRODUCTION: In Portugal, lung cancer (LC) is the first cause of cancer-related death and of death and disability combined. This study aims to analyze the overall survival (OS) and relative survival (RS) of patients diagnosed with LC in 2009-2011 by socio-demographic and tumor characteristics, and analyze sex-specific patterns. METHODS: We estimated 5-year OS using the Kaplan-Meier method and 5-year net survival through the RS framework. Cox regression modeling was used to determine the hazard ratio (HR) of death associated with each independent variable. FINDINGS: For the 11,523 cases analyzed, median 5-year OS was 264 days (95% confidence interval [CI]: 254.8-273.2), the cumulative OS was 13.6% and RS was 15.1%. Males had a lower median survival (237 days; 95% CI: 228.2-245.7) compared to females (416 days; 95% CI: 384.4-447.6) (p < 0.0001) and lower 5-year RS proportions (12.1% vs. 24.9%). RS progressively decreased with age (41.7% for age-group <40 to 7.2% for ≥80) and stage (66.6% for stage I to 2.4% for stage IV). As predictors of decreased survival, we identified male gender, increasing age >50, histologic types (squamous cell carcinoma, non-small cell lung cancer not otherwise specified, other unspecified and small cell lung cancer), and increasing stage. Compared to women, the risk of death in men was 37.7% higher (HR = 1.386; 95% CI: 1.295-1.484). CONCLUSIONS: The differences between OS and RS were small, reflecting the high lethality of LC. Male gender and older age are factors related to poor prognosis. Histology also plays a role in survival prognosis and varies with gender, but the factor related to the worst survival is stage. Although the study reflects data from a decade ago, and major changes occurred in diagnosis, staging and treatment, particularly for advanced disease, as LC mortality is strongly correlated with late stage diagnosis, all efforts should be made to secure early diagnosis and improve survival prospects.

Histopathological parameters reported in microinvasive oral squamous cell carcinoma: a systematic review.

BACKGROUND: Microinvasive oral squamous cell carcinoma (OSCCmi) is an incipient stage of oral cancer. Through this systematic review, we aim to assess patterns of histopathological outcomes reported in OSCCmi cases. MATERIAL AND METHODS: An online search in major databases was performed without period restriction, and 2,024 publications in English, Spanish and Portuguese were obtained. After screening and eligibility, 4 studies were selected. The risk of bias was assessed using Joanna Briggs Institute Critical Appraisal Checklist. A descriptive synthesis was conducted. RESULTS: All 4 publications included were retrospective, reporting a total of 116 OSCCmi patients, with a male predominance (1.6:1) and a mean age of 55.9 years. The main parameters considered for microinvasion were tumor thickness (TT) (range 4-10mm) and depth of invasion (DOI) (range 0,02-5mm). Definition, cut-off values, and assessment of microscopic features were not standardized. Other relevant measures such as perineural or lymphovascular invasion and pattern of invasive front were barely described, and cytological/architectural characteristics were not discussed. CONCLUSIONS: TT and DOI are currently the primary histopathological criteria used to define OSCCmi. Nonetheless, the outcomes of this systematic review showed the absence of standardized quantitative parameters to render the diagnosis of microinvasive OSCC. Therefore, additional studies aiming to standardize histopathological features to diagnose OSCCmi are paramount.

Mutation and SARS-CoV-2 strain competition under vaccination in a modified SIR model.

The crisis caused by the COVID-19 outbreak around the globe raised an increasing concern about the ongoing emergence of variants of the virus that may evade the immune response provided by vaccines. New variants appear due to mutation, and as the cases accumulate, the probability of the emergence of a variant of concern increases. In this article, we propose a modified susceptible, infected, and recovered (SIR) model with waning immunity that captures the competition of two strain classes of an infectious disease under the effect of vaccination with a highly contagious and deadlier strain class emerging from a prior strain due to mutation. When these strains compete for a limited supply of susceptible individuals, changes in the efficiency of vaccines may affect the behaviour of the disease in a non-trivial way, resulting in complex outcomes. We characterise the parameter space including intrinsic parameters of the disease, and using the vaccine efficiencies as control variables. We find different types of transcritical bifurcations between endemic fixed points and a disease-free equilibrium and identify a region of strain competition where the two strain classes coexist during a transient period. We show that a strain can be extinguished either due to strain competition or vaccination, and we obtain the critical values of the efficiency of vaccines to eradicate the disease. Numerical studies using parameters estimated from publicly reported data agree with our theoretical results. Our mathematical model could be a tool to assess quantitatively the vaccination policies of competing and emerging strains using the dynamics in epidemics of infectious diseases.